Clinical, Electrophysiological and Genetic Studies of Two Families with Mutations in the GDAP1 Gene

Abstract

Mutations in the gene for the ganglioside-induced-differentiation-associated-protein 1 on 8q21 were recently reported to cause autosomal recessive Charcot-Marie-Tooth sensorimotor neuropathy. We report a detailed clinical, electrophysiological and genetic study of two young patients harbouring missense GDAP1 mutations. The two patients presented severe neuropathy with an early onset. One of the mutations (Tyr279Cys) has never been hitherto reported. Electrophysiological investigations suggested a predominant axonal damage in both patients. Despite the similitude of the type of mutations and electromyographic features, the clinical course was different for the patients, highlighting the complexity of genotype/phenotype relationships among GDAP1 mutations.

Key words

Charcot-Marie-Tooth disease - GDAP1 gene - peripheral neuropathy - electromyogram

References

• 1 Ammar N, Nelis E, Merlini L. et al . Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease.  Neuromuscul Disord. 2003;  13 720-728
• 2 Baránková L, Vyhnálková E, Züchner S. et al . GDAP1 mutations in Czech families with early-onset CMT.  Neuromuscul Disord. 2007;  17 482-489
• 3 Baxter RV, Ben Othmane K, Rochelle JM. et al . Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21.  Nat Genet. 2002;  30 21-22
• 4 Ben Othmane K, Hentati F, Lennon F. et al . Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q.  Hum Mol Genet. 1993;  2 1625-1628
• 5 Bernard R, Sandre-Giovannoli A De, Delague V. et al . Molecular genetics of autosomal-recessive axonal Charcot-Marie-Tooth neuropathies.  Neuromolecular Med. 2006;  8 87-106
• 6 Cuesta A, Pedrola L, Sevilla T. et al . The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.  Nat Genet. 2002;  30 22-25
• 7 Kabzinska D, Drac H, Rowinska-Marcinska K. et al . Early onset Charcot-Marie-Tooth disease caused by a homozygous Leu239Phe mutation in the GDAP1 gene.  Acta Myol. 2006;  25 34-37
• 8 Nelis E, Erdem S, Bergh PY Van Den. et al . Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy.  Neurology. 2002;  59 1865-1872
• 9 Niemann A, Ruegg M, La Padula V. et al . Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease.  J Cell Biol. 2005;  170 1067-1078
• 10 Pedrola L, Espert A, Wu X. et al . GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria.  Hum Mol Genet. 2005;  14 1087-1094
• 11 Sevilla T, Cuesta A, Chumillas MJ. et al . Clinical, electrophysiological and morphological findings of Charcot-Marie-Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene.  Brain. 2003;  126 2023-2033
• 12 Stojkovic T, Latour P, Viet G. et al . Vocal cord and diaphragm paralysis, as clinical features of a French family with autosomal recessive Charcot-Marie-Tooth disease, associated with a new mutation in the GDAP1 gene.  Neuromuscul Disord. 2004;  14 261-264

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